EP1567150A1 - Indol-3-carboxamide, deren herstellung und therapeutische verwendung - Google Patents

Indol-3-carboxamide, deren herstellung und therapeutische verwendung

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Publication number
EP1567150A1
EP1567150A1 EP03789510A EP03789510A EP1567150A1 EP 1567150 A1 EP1567150 A1 EP 1567150A1 EP 03789510 A EP03789510 A EP 03789510A EP 03789510 A EP03789510 A EP 03789510A EP 1567150 A1 EP1567150 A1 EP 1567150A1
Authority
EP
European Patent Office
Prior art keywords
indole
methyl
group
sub
carboxamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP03789510A
Other languages
English (en)
French (fr)
Other versions
EP1567150B1 (de
Inventor
Francis Barth
Mireille Rinaldi-Carmona
Claude Vernhet
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi Aventis France
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Sanofi Aventis France
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Filing date
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Publication of EP1567150A1 publication Critical patent/EP1567150A1/de
Application granted granted Critical
Publication of EP1567150B1 publication Critical patent/EP1567150B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Definitions

  • the present invention relates to indole-3-carboxamide derivatives, to their preparation and to their therapeutic application.
  • - R2 represents a hydrogen atom or a (C ⁇ -C4) alkyl group
  • - R3 represents a halogen atom or a (C ⁇ -C4) alkyl group
  • R4 represents a hydrogen or halogen atom or a (C ⁇ -C4) alkyl- group
  • - R5 represents a group (Ci-G-palkyl or trifluoromethyl
  • - X represents a sulfur atom, a group -NHSO2- or a group -SO2-;
  • the compounds of formula (I) can also exist in the form of hydrates or of solvates, namely in the form of associations or combinations with one or more molecules of water or with a solvent . Such hydrates and solvates are also part of the invention.
  • the compounds of formula (I) may contain one or more asymmetric carbon atoms.
  • the various stereoisomers as well as the racemates are part of the invention.
  • halogen atom fluorine, chlorine, bromine or iodine
  • alkyl group a linear or branched saturated aliphatic group.
  • alkyl group a linear or branched saturated aliphatic group.
  • a monocyclic radical or a condensed or bridged di or tricyclic radical by monocyclic radical is meant a cycloalkyl such as for example cyclopentyl or cyclohexyl; by condensed or bridged di or tricyclic radical is meant, for example, bicyclo [2.2.1] heptyle, bicyclo [3.2.1] octyl, adamantyl.
  • R ⁇ represents a C5-Cg carbocyclic radical, unsubstituted or substituted one or more times with a methyl group
  • - R2 represents hydrogen or a (C ⁇ -C4) alkyl
  • - R3 represents a halogen atom or a (C1-C4) alkyl group
  • R4 represents a hydrogen or halogen atom or a (C ⁇ -C4) alkyl group
  • R5 represents a (C ⁇ -C4) alkyl
  • - X represents a sulfur atom, a group -NHSO2- or a group -SO2-; - n is equal to 2 or 3.
  • - Ri represents a 1,3,3-trimethylbicyclo [2.2.1] hept-2-yl or a bicyclo [3.2.1] oct-3 -y le; - R2 represents hydrogen or methyl;
  • R3 represents a chlorine, fluorine or bromine atom or a methyl group
  • R4 represents a hydrogen, chlorine or fluorine atom or a methyl group
  • the compounds of general formula (I) can be prepared according to the process which follows. This process is characterized in that a functional derivative of indole acid is treated.
  • an acid chloride an anhydride or alternatively the acid suitably activated for example with the benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluoro phosphate (BOP) or (1 -benzotriazolyl) oxytris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP).
  • benzotriazol-1-yloxytris dimethylamino) phosphonium hexafluoro phosphate (BOP)
  • 1- -benzotriazolyl) oxytris pyrrolidino) phosphonium hexafluorophosphate
  • reaction is carried out in an aprotic solvent such as dichloromethane, THF or DMF, in basic medium, and in the presence of a coupling agent such as BOP or dicyclohexylcarbodiimide (DCC).
  • aprotic solvent such as dichloromethane, THF or DMF
  • basic medium such as basic medium
  • a coupling agent such as BOP or dicyclohexylcarbodiimide (DCC).
  • a compound of formula (I) in which X represents an SO2 group can be prepared from a compound of formula (I) carrying the same substituents and in which X is a sulfur atom, by the action of an oxidizing agent such than metachloroperbenzoic acid (MCPB A).
  • an oxidizing agent such than metachloroperbenzoic acid (MCPB A).
  • indole-3-carboxylic acid derivatives of formula (II) are prepared from corresponding indole derivatives of formula:
  • acylating agent can be, for example, oxalyl chloride, or alternatively trichloroacetyl chloride. In the latter case, the intermediate trichloroacetyl derivative obtained is then treated successively with a strong base and then an acid to yield the desired acid.
  • indole derivatives of formula (IN) are known or prepared by methods such as those described in WO 02/42269.
  • R2 represents a hydrogen atom or a (C ⁇ -C4) alkyl group
  • R3 represents a halogen atom or a (C - [- C4) alkyl group
  • R4 represents a hydrogen or halogen atom or a (C ⁇ -C4) alkyl group
  • - R5 represents a (Ci-C4) alkyl or trifluoromethyl group
  • - X represents a sulfur atom, a group -NHSO2- or a group -SO2-;
  • - n is equal to 2 or 3.
  • Ci-C ⁇ alkyl salts and esters or the benzyl ester of the compounds of formula (II) also form part of the invention.
  • R3 represents a chlorine or bromine atom
  • R4 represents a hydrogen or chlorine atom or a methyl group
  • - X represents a sulfur atom or an NHSO2 group; - n is equal to 3; as well as their salts and alkyl esters in (C ⁇ -Cg) or benzyl ester.
  • TCE 1,1,2,2-tetrachloroethane.
  • the nuclear magnetic resonance spectra are recorded at 200 MHz in DMSO-d6.
  • the following abbreviations are used: s: singlet, d: doublet, t: triplet, m: massive, mt: multiplet, se: widened singlet, q: quatruplet, qt: quintuplet.
  • Compounds according to. the invention are analyzed by LC / UN / MS coupling (liquid chromatography / UN detection / mass spectrometry). The molecular peak (MH) and the retention time (t) in minutes are measured.
  • a Symetry Waters MS Cl 8 column marketed by Waters, of 2.1 ⁇ 50 mm, 3.5 ⁇ m, is used at room temperature, flow rate 0.4 ml / minute.
  • the eluent is composed as follows:
  • the reaction medium is poured into water then extracted successively with a KHSO4 / K2SO4 solution, with water with a 10% sodium hydroxide solution and then with a saturated NaCl solution. It is dried over Na2S ⁇ 4 and the solvents are evaporated, then chromatography a first time on silica, eluting with an AcOEt / cyclohexane mixture (7/3; v / v). The product obtained is chromatographed again on silica, eluting with AcOEt cyclohexane (7/3; v / v). 230 mg of product are obtained, mp 134-136 ° C.
  • Me represents a methyl group, t-Bu a t-butyl group.
  • the compounds according to the invention have been the subject of pharmacological tests.
  • the compounds according to the invention have shown a good in vitro affinity for the cannabinoid receptors (CB2) and a clearly weaker in vitro affinity for the cannabinoid receptors (CBj) whether they are human receptors or rodent.
  • CB2 cannabinoid receptors
  • CBj cannabinoid receptors
  • the in vitro affinity for cannabinoids CB2 expressed in the form of Ki is ⁇ less than 10 " M and the-r-contribution between the affinity for CBj receptors and that for CB2 receptors is at least 100.
  • the compounds according to the invention behave in vitro as specific agonists of human cannabinoid receptors CB2 versus CB ⁇ , they decrease the production of cAMP in cells stimulated by forskolin and this by inhibiting adenylate cyclase.
  • the tests were carried out according to the experimental conditions described by Matsuda et al., Nature 1990, 346, 561-564.
  • the compounds according to the invention have a selective agonist activity for CB2 receptors for cannabinoids.
  • the compounds according to the invention or their possible salts also have an in vivo affinity for the cannabinoid receptors CB2 present in the spleen of mice when they are administered intravenously or orally. Their activity has been demonstrated by ex vivo binding experiments of [ ⁇ H] -CP 55940. The tests were carried out according to the experimental conditions described by M. Rinaldi-Carmona et al., Life Sciences, 1995, 56, 1941-1947.
  • the compounds according to the invention can therefore be used for the preparation of medicaments, in particular medicaments which are agonists of the CB2 cannabinoid receptors.
  • the subject of the invention is medicaments which comprise a compound of formula (I) or a hydrate or a solvate of the compound of formula (I).
  • hemolytic autoimmune anemias multiple sclerosis, amyotrophic lateral sclerosis, amyloidosis, glomerulonephritis, transplant rejection, diseases affecting the plasma cell line; allergic diseases: delayed or immediate hypersensitivity, allergic rhinitis, contact dermatitis, allergic conjunctivitis; parasitic, viral or bacterial infectious diseases: AIDS, meningitis; inflammatory diseases, especially joint diseases: arthritis, rheumatoid arthritis, reactive arthritis, osteoarthritis, spondylitis, ankylosing spondylitis, undifferentiated spondylitis, gout, vasculitis, thyroiditis,
  • the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention.
  • These pharmaceutical compositions contain an effective dose of at least one compound according to the invention or a hydrate or solvate of said compound, as well as at least one pharmaceutically acceptable excipient.
  • Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
  • compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active principle of formula (I) above, or its solvate or hydrate, if any, can be administered in unit administration form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.
  • Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, lo
  • granules and oral solutions- or suspensions sublingual, buccal, intratracheal, intraocular, intranasal, inhalation administration forms, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
  • topical application one can use the compounds of the invention in creams, gels, ointments or lotions.
  • the dose of active ingredient administered per day can reach 0.01 to 20 mg / kg, in one or more doses.
  • the appropriate dosage for each patient is determined by the doctor according to the method of administration, the weight and the response of said patient.
  • the present invention also relates to a method of treatment of the pathologies indicated above which comprises the administration, to a patient, of an effective dose of a compound according to the invention or hydrates or solvates .

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EP03789510A 2002-11-29 2003-11-27 Indol-3-carboxamide, deren herstellung und therapeutische verwendung Expired - Lifetime EP1567150B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0215086 2002-11-29
FR0215086A FR2847899B1 (fr) 2002-11-29 2002-11-29 Derives d'indole-3-carboxamide, leur preparation et leur application en therapeutique
PCT/FR2003/003499 WO2004050086A1 (fr) 2002-11-29 2003-11-27 Derives d'indole-3-carboxamide, leur preparation et leur application en therapeutique

Publications (2)

Publication Number Publication Date
EP1567150A1 true EP1567150A1 (de) 2005-08-31
EP1567150B1 EP1567150B1 (de) 2009-08-12

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US (1) US7202268B2 (de)
EP (1) EP1567150B1 (de)
JP (1) JP2006509781A (de)
AT (1) ATE439128T1 (de)
AU (1) AU2003294092A1 (de)
DE (1) DE60328819D1 (de)
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FR2893615B1 (fr) * 2005-11-18 2008-03-07 Sanofi Aventis Sa Derives de 3-acylindole, leur preparation et leur application en therapeutique
US8841334B2 (en) 2006-05-31 2014-09-23 Abbvie Inc. Compounds as cannabinoid receptor ligands and uses thereof
CN101448800A (zh) 2006-05-31 2009-06-03 艾博特公司 作为大麻素受体配体的新型化合物及其用途
JP5159630B2 (ja) * 2006-09-13 2013-03-06 協和発酵キリン株式会社 縮環複素環誘導体
CN101765594A (zh) 2007-03-28 2010-06-30 雅培制药有限公司 作为大麻素受体配体的1,3-噻唑-2(3h)-亚基化合物
US7872033B2 (en) 2007-04-17 2011-01-18 Abbott Laboratories Compounds as cannabinoid receptor ligands
CN101711253A (zh) 2007-05-18 2010-05-19 雅培制药有限公司 用作大麻素受体配体的新化合物
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US20050288356A1 (en) 2005-12-29
WO2004050086A8 (fr) 2004-07-29
FR2847899A1 (fr) 2004-06-04
ATE439128T1 (de) 2009-08-15
DE60328819D1 (de) 2009-09-24
US7202268B2 (en) 2007-04-10
WO2004050086A1 (fr) 2004-06-17
JP2006509781A (ja) 2006-03-23
FR2847899B1 (fr) 2006-04-28
EP1567150B1 (de) 2009-08-12
AU2003294092A1 (en) 2004-06-23

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